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Supplementary Figure 2 from OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

Supplementary Figure 1 from OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-β. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. [Cancer Res 2008;68(13):5206–15]

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

Recent rapid improvements in laminated timber technology has led to the increased use of of wood in both mid- and high-rise construction, generally posed as a more carbon friendly alternative to concrete. However, wood is significantly more sensitive to changes in relative humidity than concrete, which may impact the sustainability and durability of mass timber buildings. Moisture cycling in particular affects not only shrinkage and swelling but also strongly influences wood creep. This sensitivity is of high concern for engineered wood used in mass timber buildings. At the same time, wood, considered as an orthotropic material, exhibits varying diffusivity in all three directions, complicating efforts to characterize its behavior. In this work, an orthotropic hygroscopic model was developed for use in laminated timber. A species database for wood sorption isotherm was created and an existing model was used to fit species-based parameters. Diffusion behavior which considers the sorption isotherm was modeled through numerical simulations, and species-dependent orthotropic diffusion parameters were identified. A database of permeability in all directions for various species was created. The resulting model is able to predict diffusion behavior in glulam and cross laminated timber (CLT) for multiple species of the lab tests. The model also predicts the moisture ranges for a CLT panel under environmental change with parameters from these sorption isotherm and diffusion databases.

Objectives: This study’s objective was to evaluate if exercise during pregnancy, a healthy diet rich in polyunsaturated fatty acids and calcium, and the mother’s educational level influenced the dental health measures of caries risk and tooth eruption of their offspring. Methods: Women with children 6 years and younger completed questionnaires regarding PA and diet (PUFA-rich, calcium-rich (Ca) dairy foods) during pregnancy and education level prior to their child’s dental examination. T-tests were used to compare exercisers and non-exercisers; correlation and regression analyses were conducted to determine relationships and predictors of child dental health, respectively. Results: Eighty-two mother-child pairs were analysed. Exercisers had trends of increased PUFA (p=0.07) and Ca-rich dairy foods (p=0.12) to non-exercisers during pregnancy. Ca-rich dairy foods during pregnancy had positive associations with primary tooth count (p=0.004), mixed surface count (p=0.02), and tooth eruption (p=0.04). Controlling for maternal education and exercise, tooth eruption was predicted by PUFA summary and cheese consumption while dairy summary predicted primary tooth count; caries risk was predicted by maternal education; primary surface caries was associated with exercise duration. Conclusion: During pregnancy, calcium-rich dairy and PUFA-rich foods influenced child tooth eruption and thus tooth count, while exercise duration was associated with primary surface caries. Maternal education was associated with lower caries risk. Our findings support educating women on calcium intake and appropriate exercise levels during pregnancy, plus oral health counseling for their child.

Suitable habitat fragment size, isolation, and distance from a source are important variables influencing community composition of plants and animals, but the role of these environmental factors in determining composition and variation of host-associated microbial communities is poorly known. In parasite-associated microbial communities, it is hypothesized that evolution and ecology of an arthropod parasite will influence its microbiome more than broader environmental factors, but this hypothesis has not been extensively tested. To examine the influence of the broader environment on the parasite microbiome, we applied high-throughput sequencing of the V4 region of 16S rRNA to characterize the microbiome of 222 obligate ectoparasitic bat flies (Streblidae and Nycteribiidae) collected from 155 bats (representing six species) from ten habitat fragments in the Atlantic Forest of Brazil. Parasite species identity is the strongest driver of microbiome composition. To a lesser extent, reduction in habitat fragment area, but not isolation, is associated with an increase in connectance and betweenness centrality of bacterial association networks driven by changes in the diversity of the parasite community. Controlling for the parasite community, bacterial network topology covaries with habitat patch area and exhibits parasite-species specific responses to environmental change. Taken together, habitat loss may have cascading consequences for communities of interacting macro- and microorgansims.

According to the World Health Organization, 83,339 laboratory-confirmed cases, including 72 deaths, of mpox (formerly known as monkeypox), have been reported from 110 locations globally as of 20 December 2022, making the disease a public health concern. Most of the cases (56,171, 67.4%) were reported from countries in North America. Limited data on vaccine effectiveness in the current mpox outbreak are available. However, the modified vaccinia virus (smallpox vaccine) has been predicted to prevent or reduce the severity of the mpox infection. The present study of systematic review and meta-analysis aimed to evaluate the modified vaccinia vaccine’s safety and efficacy on mpox by using reported randomized clinical trials. Following guidelines from the Cochrane Collaboration and PRISMA, multiple databases including PubMed, PLOS ONE, Google Scholar, British Medical Journal, and the U. S. National Library of Medicine were searched. Out of 13,294 research articles initially identified, 187 were screened after removing duplicates. Following the inclusion and exclusion criteria, the meta-analysis included ten studies with 7430 patients. Three researchers independently assessed the risk of bias in the included study. The pooled results suggest that the vaccinia-exposed group had fewer side effects when compared to the vaccinia naïve group (odds ratio: 1.66; 95% CI: 1.07–2.57; p = 0.03). Overall, the modified vaccinia has proven safe and effective in both vaccinia naïve and previously exposed groups, with higher efficacy in the previously exposed groups.

Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.

Horseshoe bats (Family Rhinolophidae) show an impressive array of morphological traits associated with use of high duty cycle echolocation calls that they emit via their nostrils (nasophonation). Delicate maxilloturbinal bones inside the nasal fossa of horseshoe bats have a unique elongated strand-like shape unknown in other mammals. Maxilloturbinal strands also vary considerably in length and cross-sectional shape. In other mammals, maxilloturbinals help direct respired air and prevent respiratory heat and water loss. We investigated whether strand-shaped maxilloturbinals in horseshoe bats perform a similar function to those of other mammals, or whether they were shaped for a role in nasophonation. Using histology, we studied the mucosa of the nasal fossa in Rhinolophus lepidus, which we compared with Hipposideros lankadiva (Hipposideridae) and Megaderma lyra (Megadermatidae). Using micro-CT scans of 30 horseshoe bat species, we quantified maxilloturbinal surface area and skull shape within a phylogenetic context. Histological results showed horseshoe bat maxilloturbinals are covered in a thin, poorly vascularized, sparsely ciliated mucosa poorly suited for preventing respiratory heat and water loss. Maxilloturbinal surface area was correlated with basicranial width, but exceptionally long and dorsoventrally flat maxilloturbinals did not show enhanced surface area for heat and moisture exchange. Skull shape variation appears to be driven by structures linked to nasophonation, including maxilloturbinals. Resting echolocation call frequency better predicted skull shape than did skull size, and was specifically correlated with dimensions of the rostral inflations, palate, and maxilloturbinals. These traits appear to form a morphological complex, indicating a nasophonatory role for the strand-shaped rhinolophid maxilloturbinals. Anat Rec, 2018. © 2018 American Association for Anatomy.

Comprising more than 1400 species, bats possess adaptations unique among mammals including powered flight, unexpected longevity given small body size, and extraordinary immunity. Some of the molecular mechanisms underlying these unique adaptations includes DNA repair, metabolism and immunity. However, analyses have been limited to a few divergent lineages, reducing the scope of inferences on gene family evolution across the Order Chiroptera. We conducted an exhaustive comparative genomic study of 37 bat species encompassing a large number of lineages, with a particular emphasis on multi-gene family evolution across immune system and metabolic genes. In agreement with previous analyses, we found lineage-specific expansions of the APOBEC3 and MHC-I gene families, and loss of the proinflammatory PYHIN gene family. We inferred more than 1,000 gene losses unique to bats, including genes involved in the regulation of inflammasome pathways such as epithelial defense receptors, the natural killer gene complex and the interferon-gamma induced pathway. Gene set enrichment analyses revealed genes lost in bats are involved in defense response against pathogen-associated molecular patterns and damage-associated molecular patterns. Gene family evolution and selection analyses indicate bats have evolved fundamental functional differences compared to other mammals in both innate and adaptive immune system, with the potential to enhance anti-viral immune response while dampening inflammatory signaling. In addition, metabolic genes have experienced repeated expansions related to convergent shifts to plant-based diets. Our analyses support the hypothesis that, in tandem with flight, ancestral bats had evolved a unique set of immune adaptations whose functional implications remain to be explored.

Recently, single-crystal Cu-Al-Mn (CAM) superelastic alloy (SEA) bars have been developed to address the shortcomings of traditional Ni-Ti SEA bars, i.e., high cost, low workability, and la...

Contaminants such as mercury are pervasive and can have immunosuppressive effects on wildlife. Impaired immunity could be important for forecasting pathogen spillover risks, as many land-use changes that generate mercury contamination also bring wildlife into close contact with humans and domestic animals. However, the interactions among contaminants, immunity, and infection are difficult to study in natural systems, and empirical tests of possible directional relationships remain rare.We capitalized on extreme mercury variation in a diverse bat community in Belize to test association among contaminants, immunity, and infection. By comparing a previous dataset of bats sampled in 2014 with new data from 2017, representing a period of rapid agricultural land conversion, we first confirmed bat species more reliant on aquatic prey had higher fur mercury. Bats in the agricultural habitat also had higher mercury in recent years. We then tested covariation between mercury and cellular immunity and determined if such relationships mediated associations between mercury and common bacterial pathogens. As bat ecology can dictate exposure to mercury and pathogens, we also assessed species-specific patterns in mercury–infection relationships.Across the bat community, individuals with higher mercury had fewer neutrophils but not lymphocytes, suggesting stronger associations with innate immunity. However, the odds of infection for hemoplasmas and Bartonella spp. were generally lowest in bats with high mercury, and relationships between mercury and immunity did not mediate infection patterns. Mercury also showed species- and clade-specific relationships with infection, being associated with especially low odds for hemoplasmas in Pteronotus mesoamericanus and Dermanura phaeotis. For Bartonella spp., mercury was associated with particularly low odds in the genus Pteronotus but high odds in the Stenodermatinae.Synthesis and application: Lower general infection risk in bats with high mercury despite weaker innate defense suggests contaminant-driven loss of pathogen habitat (i.e., anemia) or vector mortality as possible causes. Greater attention to these potential pathways could help disentangle relationships among contaminants, immunity, and infection in anthropogenic habitats and help forecast disease risks. Our results also suggest contaminants may increase infection risk in some taxa but not others, emphasizing the importance of considering surveillance and management at different phylogenetic scales.

Arthropod ectoparasites generally have nutrient-poor diets and are dependent on their bacterial symbionts for nutrient acquisition, development, and immune response initiation. As the body of research on parasite-microbiome interactions continues to grow, it is becoming more apparent that the parasite is not an island that physically and biologically constrains the microbiome. Suitable habitat fragment size, isolation, and distance from a source are important variables influencing community composition of plants and animals, but the role of the environment in determining composition and variation of host-associated microbial communities is poorly known. It is hypothesized that evolution and ecology of an arthropod parasite will influence its microbiome more than broader environmental factors, but this hypothesis has not yet been tested. To compare the relative influence of the broader environment to that of phylogenetic constraint on the microbiome, we applied high-throughput sequencing of the V4 region of 16S rRNA from 222 obligate ectoparasitic bat flies (Streblidae and Nycteribiidae) collected from 155 bats (representing six species) from ten habitat fragments in the Atlantic Forest of Brazil. We find that parasite species identity is the strongest driver of microbiome composition. To a lesser extent, reduction in habitat fragment area is associated with a reduction in connectance of microbial interaction networks and an increase in modularity, but size-independent measures of network topology and bacterial taxon richness do not show an impact of the environment. Instead, habitat fragments that support more diverse bat and bat fly communities also support more connected bacterial interaction networks.

Today, the world is facing the challenge of a major pandemic due to COVID-19, which has caused more than 6.1 million cases of infection and nearly 370,000 deaths so far. Most of the deaths from the disease are clustered in the older population, but the young and children are not spared. In this context, there is a critical need to revisit the formula for calculating potential years of life lost (PYLL). Data on age-specific deaths due to COVID-19 in three countries, including the United States (US), Italy, and Germany, were evaluated. New York State, as a significant outlier within the US, was also included. PYLLs in the US were five times as high as those of Italy. Compared with Germany, PYLLs in Italy were 4 times higher, and the rates in the US were 23, 25, and 18 times higher when using upper age limits of 70, 75, and 80, respectively. Standardized PYLLs in New York were 2 times as high as the rates in Italy, and 7 to 9 times as high as PYLLs in Germany. The revised formula of PYLL, using an upper limit of age 80, is recommended to accurately measure premature deaths due to a major disastrous disease such as COVID-19.

Most emerging pathogens can infect multiple species, underscoring the importance of understanding the ecological and evolutionary factors that allow some hosts to harbor greater infection prevalence and share pathogens with other species. Investigating such factors can inform surveillance efforts and help forecast disease emergence. However, our understanding of pathogen jumps is primarily based around viruses, despite bacteria accounting for the greatest proportion of zoonoses. Because bacterial pathogens in bats (Order: Chiroptera) can have conservation and human health consequences, studies that examine the ecological and evolutionary drivers of bacterial prevalence and barriers to pathogen sharing are crucially needed. We here studied hemotropic Mycoplasma spp. (i.e., hemoplasmas) across a species-rich bat community in Belize over two years. Across 469 bats spanning 33 species, half of individuals and two-thirds of species were hemoplasma positive. Infection prevalence was higher for males, heavier species, and those with larger colony sizes. Hemoplasmas displayed high genetic diversity (21 novel genotypes) and strong host specificity. Evolutionary patterns supported co-divergence of bats and bacterial genotypes alongside phylogenetically constrained host shifts. Bat species centrality to the network of shared hemoplasma genotypes was phylogenetically clustered and unrelated to prevalence, further suggesting rare—but detectable—bacterial sharing between species. Our study highlights the importance of using fine phylogenetic scales when assessing host specificity and suggests phylogenetic similarity may play a key role in host shifts for not only viruses but also bacteria. Such work more broadly contributes to increasing efforts to understand cross-species transmission and epidemiological consequences of bacterial pathogens.

Occupational exposure to swine has been associated with increased Staphylococcus aureus carriage, including antimicrobial-resistant strains, and increased risk of infections. To characterize animal and environmental routes of worker exposure, we optimized methods to identify S. aureus on operations that raise swine in confinement with antibiotics (industrial hog operation: IHO) versus on pasture without antibiotics (antibiotic-free hog operation: AFHO). We associated findings from tested swine and environmental samples with those from personal inhalable air samplers on worker surrogates at one IHO and three AFHOs in North Carolina using a new One Health approach. We determined swine S. aureus carriage status by collecting swab samples from multiple anatomical sites, and we determined environmental positivity for airborne bioaerosols with inhalable and impinger samplers and a single-stage impactor (ambient air) cross-sectionally. All samples were analyzed for S. aureus, and isolates were tested for antimicrobial susceptibility, absence of scn (livestock marker), and spa type. Seventeen of twenty (85%) swine sampled at the one IHO carried S. aureus at >1 anatomical sites compared to none of 30 (0%) swine sampled at the three AFHOs. All S. aureus isolates recovered from IHO swine and air samples were scn negative and spa type t337; almost all isolates (62/63) were multidrug resistant. S. aureus was recovered from eight of 14 (67%) ambient air and two (100%) worker surrogate personal air samples at the one IHO, whereas no S. aureus isolates were recovered from 19 ambient and six personal air samples at the three AFHOs. Personal worker surrogate inhalable sample findings were consistent with both swine and ambient air data, indicating the potential for workplace exposure. IHO swine and the one IHO environment could be a source of potential pathogen exposure to workers, as supported by the detection of multidrug-resistant S. aureus (MDRSA) with livestock-associated spa type t337 among swine, worker surrogate personal air samplers and environmental air samples at the one IHO but none of the three AFHOs sampled in this study. Concurrent sampling of swine, personal swine worker surrogate air, and ambient airborne dust demonstrated that IHO workers may be exposed through both direct (animal contact) and indirect (airborne) routes of transmission. Investigation of the effectiveness of contact and respiratory protections is warranted to prevent IHO worker exposure to multidrug-resistant livestock-associated S. aureus and other pathogens.

e18541 Background: With increasing numbers of newly approved cancer immunotherapy regimens, research is needed to understand whether these costly treatments are equally used by all patients who could benefit from them. The aim of this systematic review was to identify variables linked to whether patients diagnosed with cancer were treated with checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. Methods: Using the PICO (Patient, Intervention, Comparison, Outcome) framework, we conducted a systematic review searching Medline (New PubMed), Embase.com, and the Cochrane Library (Wiley) for papers published in English between January 1, 1997 and July 27, 2020. Inclusion criteria were: 1) primary, peer-reviewed research article; and 2) article reported variables associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Seven coders independently reviewed titles, abstracts, full texts, and extracted data. The systematic review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results: In total, 5958 titles and abstracts and 134 full texts were screened. Sixteen studies were included in final analyses. All were conducted in the United States using data from national databases (N = 15) or electronic medical records (N = 1). Eleven were cross-sectional, and 5 were cohort studies. Studies looked at melanoma (N = 10), non-small cell lung cancer (N = 3), renal cell carcinoma (N = 2), colorectal cancer (N = 1), prostate cancer (N = 1), and hepatobiliary cancer (N = 1). Studies looked at nivolumab (N = 1), pembrolizumab (N = 1), ipilimumab (N = 1), and sipuleucel-T, (N = 1), and 12 studies did not specify medication names. Treatment facility characteristics (N = 9), geographic location within the United States (N = 1), locale classification (N = 2), distance to treatment facility (N = 2), insurance type (N = 9), age (N = 7), race (N = 5), sex (N = 1), income (N = 4), neighborhood educational attainment (N = 2), comorbidities (N = 6), disease stage (N = 1), metastases (N = 3), clinical trial participation (N = 1), recency of diagnosis (N = 2), other treatments received (N = 3), and lesion characteristics (N = 1) were reported to be associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Other studies found that insurance type (N = 1), race (N = 3), sex (N = 1), other treatments received (N = 1), and lesion characteristics (N = 1) were not associated with receiving checkpoint inhibitors or CAR T-cell therapy. Conclusions: Findings provide evidence of disparate access to checkpoint inhibitors and CAR T-cell therapy. More studies are necessary to thoroughly understand how the factors highlighted in our findings intersect to create and maintain disparities in cancer treatment. This level of information is necessary to create interventions that promote equitable access to novel cancer immunotherapies.

The Mid-Atlantic Microbiome Meet-up (M3) organization brings together academic, government, and industry groups to share ideas and develop best practices for microbiome research. In January of 2018, M3 held its fourth meeting, which focused on recent advances in biodefense, specifically those relating to infectious disease, and the use of metagenomic methods for pathogen detection. Presentations highlighted the utility of next-generation sequencing technologies for identifying and tracking microbial community members across space and time. However, they also stressed the current limitations of genomic approaches for biodefense, including insufficient sensitivity to detect low-abundance pathogens and the inability to quantify viable organisms. Participants discussed ways in which the community can improve software usability and shared new computational tools for metagenomic processing, assembly, annotation, and visualization. Looking to the future, they identified the need for better bioinformatics toolkits for longitudinal analyses, improved sample processing approaches for characterizing viruses and fungi, and more consistent maintenance of database resources. Finally, they addressed the necessity of improving data standards to incentivize data sharing. Here, we summarize the presentations and discussions from the meeting, identifying the areas where microbiome analyses have improved our ability to detect and manage biological threats and infectious disease, as well as gaps of knowledge in the field that require future funding and focus. Electronic supplementary material The online version of this article (10.1186/s40168-018-0582-5) contains supplementary material, which is available to authorized users.

The pre-illness basal mean arterial BP (MAP) is an important reference point to gauge the degree of relative hypotension among unwell patients. We aimed to assess mean bias, correlation, and agreement between basal MAP measured during nighttime ambulatory BP monitoring (ABPM) and basal MAP estimated using a standardized protocol.For a cohort of 137 consecutive patients, aged ≥40 years, who recently underwent ABPM, a blinded investigator estimated basal MAP from up to five most recent clinic BP measurements. Both basal MAP values, measured and estimated, were compared pairwise for each participant.We traced a median of 4 [interquartile range 3-5] previous BP measurements per patient over a median period of 132 [interquartile range 55-277] days up until the ABPM test. The estimated basal MAP (mean 88 ± 8 mmHg) was linearly related (Pearson's r = 0.41, p = 0.0001) to the measured basal MAP (mean 88 ± 12 mmHg). Bland-Altman plot revealed a mean bias of 0.3 mmHg with agreement limits of ±22 mmHg.The mean bias between estimated and measured values for basal MAP was insignificant and modest. When a recent nighttime ABPM is unavailable, a protocol based on recent clinic BP readings can be used to estimate patient's basal MAP.Australian New Zealand Clinical Trials Registry ACTRN12613001382763.

It has been recorded that one of the possible causes that eventually escalated into the 1857 manslaughter at Mountain Meadows in Southern Utah was the poisoning of an open spring by the Fancher–Baker party as they crossed the Utah territory on their way from Arkansas to California. Historical accounts report that a number of cattle died, followed by human casualties from those that came in contact with the dead animals. Even after the Arkansas party departed, animals continued to perish and people were still afflicted by some unknown plague. Proctor Hancock Robison, a local 14-year-old boy, died shortly after skinning one of the “poisoned” cows. A careful review of the historical records, along with the more recent scientific literature, seems to exclude the likelihood of actual poisoning in favor of a more recent theory that would point to the bacterium Bacillus anthracis as the possible cause of human and animal deaths. In order to test this hypothesis, Proctor’s remains were exhumed, identified through mitochondrial DNA analysis, and tested for the presence of anthrax spores. Although preliminary testing of remains and soil was negative, description of the clinical conditions that affected Proctor and other individuals does not completely rule out the hypothesis of death by anthrax. Electronic supplementary material The online version of this article (doi:10.1007/s00414-012-0681-y) contains supplementary material, which is available to authorized users.

This Article examines both constitutional and practical problems with proposed regulation to require corporate officers to disclose health problems to shareholders. In doing so, the Article addresses the following questions, which are especially timely given the recent controversy surrounding Apple CEO Steve Jobs: To what extent should officers of public companies be required to disclose personal health problems to shareholders? Does a timely failure to disclose such information constitute securities fraud if the stock price is adversely affected once the information becomes public? Can shareholders' rights to accurate information relevant to a company's likely future performance trump an officer's right to privacy? To what extent do the answers to these questions depend on how closely the officer's identity is aligned with his/ her brand, i.e., how "iconic" the officer is perceived to be? Are these issues for regulators to address ex ante or the courts to handle ex post? And in either case, can an objective rights-balancing framework be developed?

Fecal indicator microbes, such as enterococci, are often used to assess potential health risks caused by pathogens at recreational beaches. Microbe levels often vary based on collection time and sampling location. The primary goal of this study was to assess how spatial and temporal variations in sample collection, which are driven by environmental parameters, impact enterococci measurements and beach management decisions. A secondary goal was to assess whether enterococci levels can be predictive of the presence of Staphylococcus aureus, a skin pathogen. Over a ten-day period, hydrometeorologic data, hydrodynamic data, bather densities, enterococci levels, and S. aureus levels including methicillin-resistant S. aureus (MRSA) were measured in both water and sand. Samples were collected hourly for both water and sediment at knee-depth, and every 6 h for water at waist-depth, supratidal sand, intertidal sand, and waterline sand. Results showed that solar radiation, tides, and rainfall events were major environmental factors that impacted enterococci levels. S. aureus levels were associated with bathing load, but did not correlate with enterococci levels or any other measured parameters. The results imply that frequencies of advisories depend heavily upon sample collection policies due to spatial and temporal variation of enterococci levels in response to environmental parameters. Thus, sampling at different times of the day and at different depths can significantly impact beach management decisions. Additionally, the lack of correlation between S. aureus and enterococci suggests that use of fecal indicators may not accurately assess risk for some pathogens.

Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-β. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. [Cancer Res 2008;68(13):5206–15]